One form of energy activated therapy is photodynamic therapy (PDT). PDT has been applied to the vascular system to treat atheroscleotic lesions and restenotic lesions in vivo.
PDT is performed by first administering a photosensitive compound systemically or topically, followed by illumination of the treatment site at a wavelength or waveband which closely matches the absorption spectra of the photosensitizer. In doing so, singlet oxygen and other reactive species are generated leading to a number of biological effects resulting in cytotoxicity. The depth and volume of the cytotoxic effect in tissue depends on the complex interactions of light penetration in tissue, the photosensitizer concentration and cellular location, and availability of molecular oxygen.
Vascular lesions are typically treated by light delivered from within the vessel by a fiberoptic probe as described by Mackie et al (Lasers in Surgery and Medicine 11:535-544 (Wiley-Liss, Inc. 1991). Since light is delivered from within the lumen of the vessel, the vessel by necessity must be punctured in order to introduce the optical fiber. Puncture of an arterial vessel is associated with various medical risks including, downstream embolization from intravascular dislodgement of plaque or other debris; bleeding of the puncture site at the skin or vessel; heparinization may cause bleeding or other side effects; intimal flap from passage of the optical fiber causing downstream infarction; repeat procedures pose increased total risk; infection from the optical fiber; thrombosis of the treated vessel; aneurysm formation; and perforation of the vessel wall. Furthermore, invasive PDT has other disadvantages such as inability to treat small vessel disease where the vessel(s) cannot be treated because the vessel diameter is too small and where it is unsafe to subject the patient to an invasive procedure which may increase risk of complications especially where infection and bleeding disorders pre-exist.
A large number of PDT light sources and methods of use have been described. However, reports describing the sources and effects of transcutaneous light delivery for PDT purposes are more limited. It has generally been accepted that the ability of a light source external to the body to cause clinically useful cytotoxicity is limited in depth to a range of 1-2 cm or less depending on the photosensitizer. Treatment of superficial tumors in this manner may be associated with inadvertent skin damage due to accumulation of the photosensitizer in the skin which is a property of all systemically administered sensitizers in clinical use. For example, clinically useful porphyrins such as Photophrin® (QLT, Ltd. brand of sodium porfimer) are associated with photosensitivity lasting up to 6 weeks. Purlytin®, which is a purpurin and Foscan® which is a chlorin sensitize the skin for several weeks. Indeed, efforts have been made to develop photoprotectants to reduce skin photosensitivity (see: Dillon et al., Photochemistry and Photobiology, 48(2): 235-238, 1988; and Sigdestad et al. British J. of Cancer, 74:S89-S92, 1996). In fact, PDT protocols involving systemic administration of photosensitizer require that the patient avoid sunlight and bright indoor light to reduce the chance of skin phototoxic reactions.
Recently, it has been claimed that with a sufficiently intense laser external light source causing two-photon absorption by a photosensitizer, it is theoretically possible to cause a very limited volume of cytotoxicity transcutaneously at greater depths. However, no clinical studies exist to support this contention. One would expect that the passage of an intense beam of light through the skin would lead to the same risk of injury to non-target tissues, such as skin and subcutaneous tissue, if used in conjunction with a systemically administered photosensitizer.
For example, one PDT modality discloses the use of an intense laser source to activate drug within a precisely defined boundary (see: Fisher et al., “Method for improved selectivity in photo-activation of molecular agents”, U.S. Pat. No. 5,829,448). The two-photon methodology requires a high power laser for drug activation with a highly collimated beam that requires a high degree of spatial control. For a large tumor this treatment is not practical since the beam would have to be swept across the skin surface in some sort of set, repeatable pattern over time. Patient or organ movement would be a problem, because the beam could become misaligned. Non-target tissue or skin and subcutaneous tissue photosensitivity is not addressed in the literature available. Any sensitizer in the path of the beam would be activated and cause unwanted collateral tissue damage. The present disclosure is a one-photon method and therefore teaches away from the two-photon method. Further, the present invention teaches and enables the prolonged exposure at a lower fluence rate, which promotes the protection of non-target tissue or skin and subcutaneous normal tissue and reduces collateral tissue damage.
Other modalities have employed the use of low total fluence of PDT delivered over a short time period to avoid skin photoactivation and the use of drug administration timing methods to enable destruction of small tumors in animals (see: U.S. Pat. No. 5,705,518 (Richter et al.). However, the present disclosure teaches away from this method in order to enable large total fluence PDT, but at a lower fluence rate, which enables the treatment of larger tumor volumes. Richter et al. further fails to teach or disclose the suggestion of a targeting scheme as presently disclosed.
In the event that the target lesion lies below an intact cutaneous layer, the main drawbacks of all transcutaneous illumination methods, whether they be external laser or external nonlaser light sources, are: 1) the risk of damage to non-target tissues, such as the more superficial cutaneous and subcutaneous tissues overlying the target lesion, 2) limitation of treatment volume, and 3) limitation of treatment depth. Damage to normal tissue between the light source and the target occurs due to the uptake of photosensitizer by the skin and other tissues overlying the lesion with resultant unwanted photoactivation in these tissues. The consequences of inadvertent skin damage caused by transcutaneous light delivery to a subcutaneous lesion may include severe pain, serious infection, and fistula formation. The limited volume of a target lesion that can be clinically treated and the limitations of the light penetration below the skin surface in turn have limited clinical transcutaneous PDT to superficial, thin lesions.
Clearly, there would be significant advantage to a completely noninvasive form of PDT directed to subcutaneous vascular lesions which avoids the inadvertent activation of photosensitizer in skin and intervening tissues and also avoids damaging the vessel walls. To date, this feasibility has not been clinically demonstrated nor realized. Only in animal studies utilizing mice or other rodents with very thin cutaneous tissue layers, have very small superficial subcutaneous malignant tumors been treated. These in vivo studies do not enable or teach the safe application of transcutaneous light sources to treat atherosclerotic lesions and restenotic lesions in humans, however.
This invention further discloses the selective binding of the photosensitizing agent to specific target tissue antigens, such as those found on the surface of or within vascular lesions. This targeting scheme decreases the amount of sensitizing drug required for effective therapy, which in turn reduces the total fluence, and the fluence rate needed for effective photoactivation. For example, the highly specific uptake of photosensitizer in atherosclerotic vessels using the avidin-biotin system would result in reduced or no skin uptake enabling safe transcutaneous photoactivation. While there are several reports in the scientific literature of utilizing the specificity of the binding between biotin and streptavidin to target tumor cells, there are no reports utilizing this ligand-receptor binding pair aimed at vascular lesions nor in conjunction with prolonged PDT light exposure (see, for example: Savitsky et al., SPIE, 3191: 343-353, 1997; and Ruebner et al., SPIE, 2625: 328-332, 1996). In a non-PDT modality, the biotin-streptavidin-receptor binding pair has also been used as tumor targeting conjugates with radionuclides (see: U.S. Pat. No. 5,630,996 (Reno et al.) and with monoclonal antibodies (see: Casalini et al.; J. Nuclear Med., 38(9): 1378-1381, 1997) and U.S. Pat. No. 5,482,698 (Griffiths)).
Other ligand-receptor binding pairs have been used in PDT for targeting tumor antigens, but also fail to teach their use in conjunction with blood vessel targeting or treatment of atheroscleotic and restenotic lesions (see: for example, Mew et al., J. of Immunol., 130(3): 1473-1477, 1983)
A light source far less intense than a high powered laser is used (see: W. G. Fisher, et al., Photochemistry and Photobiology, 66(2): 141-155, 1997). The present disclosure teaches the unexpected use of a low power non-coherent light source utilized for longer than about 2 hours to increase photoactivation depth. This teaches away from the use of a high powered, brief exposure using collimated light as disclosed in W. G. Fisher, et al., Photochemistry and Photobiology, 66(2):141-155, 1997.
Clearly, there is a need to improve the method of transcutaneous PDT to enable the safe and practical application of transcutaneous light to vascular lesions in large and small blood vessels without risking damage to non-target tissues, such as skin and normal subcutaneous tissue. The present disclosure teaches a method of photoactivation and photosensitizer construct which improves on the prior art by enabling PDT induced cytotoxicity on both macro- and microscopic scales without risk to the cutaneous layer. Also, the therapeutic index is enhanced due to a specific targeting scheme.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein.